| | Adjuvant endocrine therapy in postmenopausal breast cancer patients: Does hormone receptor status influence decision-making?Accepted 7 January 2010. published online 04 February 2010.
Corrected Proof Abstract Hormonal therapy, such as tamoxifen (TAM), is the cornerstone of adjuvant treatment for women with surgically resected early breast cancer that is hormone receptor-positive (HR+), typically defined by breast tumors that express the estrogen receptor (ER), the progesterone receptor (PgR), or both. TAM can have both estrogen-antagonistic and estrogen-agonistic effects, and expression of growth factor receptors such as human epidermal growth factor receptor (HER)2 in breast cancer is associated with the development of TAM resistance. Studies also suggest that a lack of PgR expression in tumors with positive ER status may be associated with increased growth factor expression, a more aggressive tumor phenotype, and TAM resistance. The aromatase inhibitors (AIs) anastrozole, letrozole, and exemestane have proven more effective than TAM as adjuvant hormonal therapy in postmenopausal women with HR+ disease. Some translational studies have also begun to investigate the efficacy of hormonal therapy according to PgR or HER2 status of the tumor. The AIs have proven to be an attractive option for patients across a broad spectrum of receptor expression profiles, and the potential for combination therapy using AIs and specific growth factor inhibitors is also under investigation. 1. Introduction  Breast cancer continues to be one of the most commonly diagnosed cancers in females, accounting for about 30% of new cases in Europe and about 8% of cancer-related deaths [1]. Hormone receptor (HR) status is an important consideration for patients with breast cancer, and about three fourths of patients with newly diagnosed breast cancer can be characterized as HR+ [2], [3]. HR+ status is generally defined as immunohistochemical (IHC) positivity for estrogen receptor (ER+), progesterone receptor (PgR+), or both [2]. Approximately 65% of breast cancers are ER+/PgR+, smaller percentages are ER+/PgR− (∼10%) and ER−/PgR+ (∼5%), and the remaining 25% are double negative (ER−/PgR−) or of “unknown” status [2]. Estrogen-bound ER functions as a transcription factor that regulates the expression of other genes, including those involved in cell cycle progression; thus, ER plays a major role in the proliferation of normal and neoplastic breast epithelial cells [4]. PgR, when bound with progesterone, also acts as a transcriptional regulator controlling the expression of multiple target genes in breast and other tissues such as the uterus and ovary. Thus, PgR also plays a pivotal role in the development and in the tumorigenesis of these tissues [5]. The PgR is subject to regulation by estrogen, and it has been shown that the activation of growth factor receptor pathways can lead to reduced PgR expression via ER-independent mechanisms [6], [7], [8]. Hormonal therapies that antagonize the activity of estrogen and progesterone have been the cornerstone of adjuvant treatments for endocrine-responsive breast cancer. Adjuvant therapy with tamoxifen (TAM) has been demonstrated to significantly reduce both disease recurrence and death from breast cancer in women with ER+ disease receiving about 5 years of therapy, compared with those receiving no treatment [9]. Human epidermal growth factor receptor 2-positive (HER2+) and PgR− disease, however, can show some degree of resistance to TAM [10], [11], [12]. Recently, the aromatase inhibitors (AIs) anastrozole (ANA), letrozole (LET), and exemestane (EXE) have been compared with TAM as initial adjuvant therapy in postmenopausal women (PMW) in the Arimidex, Tamoxifen Alone or in Combination (ATAC) and Breast International Group (BIG) 1-98 trials, and as switch therapy following 2–3 years’ prior treatment with TAM in the Intergroup Exemestane Study (IES) [13], [14], [15]. These studies have demonstrated superiority of all three AIs over TAM in terms of disease-free survival (DFS) for PMW with HR+ disease. Observational studies further suggest that the use of AIs relative to TAM as hormonal therapy in PMW with early breast cancer (EBC) has increased markedly in the last few years [16], [17]. All of the major AI trials have examined the impact of HR status in the primary publications by subgroup analysis, stratifying according to ER and PgR expression [13], [14], [15]. In the case of BIG 1-98 and ATAC, analyses were also conducted in central laboratories [18], [19]. The vast majority of patient populations across the major AI trials presented with ER+/PgR+ tumors (about 57–87%), while smaller percentages of tumors were ER+/PgR− (Table 1) [14], [15], [19], [20]. In this review, we use available sources from PubMed and large congresses to identify clinical trials with TAM, AIs, and/or targeted therapies across different adjuvant treatment settings, with an emphasis on the impact of ER PgR and HER2 expression on the efficacy of endocrine treatment. The Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial comparing EXE with TAM as initial adjuvant therapy was excluded, because public data on treatment efficacy according to PgR and HER2 status are not yet available [21]. In addition, we examine the potential utility of these biomarkers in treatment selection among the available hormonal adjuvant therapies. 2. Receptors and recurrence risk in breast cancer 2.1. ER and PgR ER and PgR expression in breast tumors is known to be both prognostic and predictive, although the prognostic value may be difficult to assess because of the confounding effects of adjuvant TAM [22]. Studies have demonstrated that the natural history of breast cancer, with regard to recurrence risk, changes over time. In patients receiving a variety of adjuvant therapies (chemotherapy with or without TAM, hormonal therapy, combination hormonal/chemotherapy, or no therapy), overall recurrence risk is greater for ER− than ER+ patients. In ER− patients, the greatest risk occurs within the first 5 years after surgery, whereas in ER+ patients, the greatest risk occurs after 5 years postsurgery [23], [24]. Recurrence risk therefore continues beyond 5 years after diagnosis [23], [25]. The prognostic/predictive value of a single HR+ phenotype (i.e., ER+/PgR− or ER−/PgR+) is still the object of research. Although some authors question the value of assessing PgR status [26], others support PgR assessment [27], [28], [29]. An analysis of a large series of primary invasive breast carcinomas (1944 cases), which focused on the single-positive subgroups (i.e., ER−/PgR+ and ER+/PgR−), found that when compared with the double-negative phenotype, ER+/PgR− tumors had a better prognosis, whereas no such finding was observed in the case of ER−/PgR+ tumors [30]. In addition, among the group of patients with ER+ tumors who received adjuvant hormonal therapy, the loss of PgR expression (i.e., ER+/PgR−) was an independent predictor of recurrence and shorter survival [30]. 3. Influence of hormone receptors and HER2 on efficacy 3.1. TAM Results of the Oxford meta-analysis of adjuvant trials have established the benefit, both in terms of DFS and overall survival (OS), of adjuvant TAM treatment (20–40 mg/day p.o.) compared with no treatment in patients with ER+ disease [9], [36]. Reductions in mortality and recurrence were comparable in women with ER+/PgR+ and ER+/PgR− disease [36]. Thus, the TAM benefits were irrespective of PgR status [9]. Nonetheless, variations in PgR measurements between studies may confound such results in large meta-analyses. In a study of two large databases with identical central PgR measurements, multivariate analysis showed that both ER and PgR were independent significant predictors of DFS and OS among patients receiving adjuvant endocrine therapy, with TAM (dose not specified) accounting for 95–97% of endocrine therapy [37]. A study of 758 breast cancer patients receiving TAM (dose not specified) for 3–5 years, with a median follow-up of 40 months, found no significant difference in DFS between ER+/PgR+ and ER+/PgR− patients (P=0.1374); however; a difference in OS was observed (P=0.0102), with the latter group having poorer survival [11]. The groups were well matched for age, tumor size, lymph node status, and other parameters, except that ER+/PgR− patients were more frequently postmenopausal. Interestingly, when the groups were stratified by age, a significant difference in DFS (P=0.0484) and OS (P=0.0009) was observed in the oldest group (>60 years) [11]. This result indicated a greater efficacy of TAM in the older ER+/PgR+ patients compared with the ER+/PgR− patients. This finding could be related to a low estrogen level and a low activity of ER in older patients. This patient population may benefit from AIs, possibly in combination with inhibitors of growth factor signaling pathways (see below) [11]. A large database study analyzed the impact of PgR as well as HER1 and HER2 status in 31,415 patients with ER+/PgR+ tumors and 13,404 patients with ER+/PgR− tumors, 11,399 of whom received endocrine therapy (97% TAM; dose not specified) [12]. Compared with ER+/PgR+ tumors, ER+/PgR− tumors were more frequent in older patients (>50 years), were larger, had more involved lymph nodes, had lower levels of ER (Fig. 1A), had higher proliferation rates (Fig. 1B), and were more likely to express HER1 (Fig. 1C) and HER2 (Fig. 1D). Of note, patients with HER1+ or HER2+ tumors had a higher risk of recurrence on TAM, but the risk varied according to PgR expression [12]. In ER+/PgR+ patients, neither HER1 nor HER2 overexpression was associated with DFS or OS, while in patients with ER+/PgR− tumors, both HER1 and HER2 expression were associated with poorer DFS (for HER1, hazard ratio [HR], 2.4, P=0.036; for HER2, HR, 2.6, P=0.022), and HER2 was associated with poorer OS (HR, 2.2; P=0.05). Another similar series failed to find an effect of ER+/PgR− status on TAM (10mg twice daily p.o.) benefit, despite a higher percentage of ER+/PgR− tumors expressing growth factor receptors (HER1 and HER2) [38]. These findings suggest that in ER+ tumors, a lack of PgR expression may identify a subset of patients with a more aggressive phenotype, higher levels of HER1 and HER2, and a greater likelihood for TAM resistance. 3.2. AIs AIs act through a different mechanism than TAM; AIs inhibit the conversion of peripheral androgens to estrogen, thereby reducing plasma estrogen levels to near undetectable levels [39]. The increased potency of AIs has consistently translated into superiority in improving DFS compared with TAM [13], [14], [40]; thus, AIs have become a standard adjuvant treatment for PMW with HR+ EBC. In addition, LET appears to be the most potent AI, suppressing estrone, estradiol, and estrone sulfate by 98.8%, 95.2% and 98.9%, respectively [41], [42]. Interestingly, in addition to the superior suppression of plasma estrogen, LET has superior potency for the suppression of tissue estrogen [42]. 3.3. Initial adjuvant therapy Upfront adjuvant AI therapy using 5 years of ANA or LET versus TAM has been investigated in the ATAC and BIG 1-98 trials, respectively [13], [14]. In these trials, randomization occurred before the initiation of adjuvant therapy, and analyses included all events during the 5-year period. This upfront trial population thus includes patients who are at risk for early relapse during the first 2–3 years of adjuvant therapy [43]. Importantly, early relapses are predominantly distant metastases (DM), which are associated with increased mortality [43], [44], [45], [46]. Early events are investigated in upfront trials, as patients at higher risk populate these trials; however, it should be noted that in the BIG 1-98 trial, only 3.7% of patients relapsed in the first 24 months. Initial adjuvant therapy with LET (2.5mg daily p.o.) was compared with TAM (20mg daily p.o.) in the BIG 1-98 trial in PMW with ER+ and/or PgR+ invasive breast cancer [14]. BIG 1-98 is different from other AI trials, because it was the only trial with a comprehensive prospective central collection of tumor samples, and it was coordinated by the International Breast Cancer Study Group (IBCSG), an independent academic cooperative group. Biopsy samples were collected from 6549 patients, 82% of the enrolled population (N=8010) [18]. Overall results from BIG 1-98 demonstrated a profound early prevention of DM (HR, 0.73; 95% confidence interval [CI], 0.60–0.88; P=0.001), which recent results suggest translates into an emerging survival benefit with LET therapy in the intent-to-treat (ITT) population (HR, 0.87; 95% CI, 0.75–1.02; P=0.08) [14], [47]. When excluding 619 patients who elected to cross over to LET after the IBCSG unblinded the TAM arm because of the superior efficacy of LET (censored analysis), the survival benefit was more pronounced than that seen in the ITT analysis (5-year OS: 91.8% vs. 90.2%, HR, 0.81; 95% CI, 0.69–0.94) [47]. Another distinguishing feature of BIG 1-98 was the central review analysis of efficacy according to ER and PgR as well as HER2 status [18], [48]. In BIG 1-98, with a median follow-up of 51 months, an analysis of locally assessed ER and PgR status in patients assigned to monotherapy with LET or TAM (N=4922) reported a benefit of LET over TAM in all patients, regardless of PgR status (Table 2) [15], [19], [20], [49]. Central review of patients receiving monotherapy was carried out for 3807 patients in BIG 1-98. Of this population, 3596 patients were assessable for ER expression by central review. There was no evidence of a differential treatment effect according to ER expression level (Fig. 2A) [18]. There was a significant benefit in DFS (HR, 0.72; 95% CI, 0.60–0.86) in favor of LET for patients with ER-expressing tumors versus patients with ER-absent tumors (HR, 1.32; 95% CI, 0.63–2.78). Because of the poor outcome of patients with ER− tumors (Fig. 2A), the analysis of the predictive value of PgR was limited to 3533 ER+ tumors, of which 3508 had assessable PgR expression. In contrast to ER expression, PgR expression was significantly associated with better DFS (P<0.0001) (Fig. 2B). There was a benefit in DFS in favor of LET both for patients with PgR− tumors and those with PgR+ tumors (Table 3), with no statistical heterogeneity in treatment effect according to level of PgR expression (P=0.47 for interaction) [18], [50]. | | |  | | | | | | |
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| N | 4922 | 6241 | 4724 | 5187 | | | Median follow-up | 51 months | 68 months | 55.7 months | 30 months | | | ER+ | NR | NR | 0.75 (0.64–0.87) | NR | | | ER+/PgR+ | 0.83 (0.68–1.02), P=0.07 | 0.84 (0.69–1.02), P=0.07 | 0.77 (0.63–0.94) | 0.49 (0.36–0.67) | | | ER−/PgR+ | NR | 0.79 (0.43–1.47), P=0.5 | NR | 0.56 (0.15–2.12) | | | ER+/PgR− | 0.92 (0.69–1.22), P=0.55 | 0.43 (0.31–0.61), P<0.0001 | 0.73 (0.53–1.00) | 1.21 (0.63–2.34) | | | ER+/PgR unknown | 0.77 (0.57–1.04), P=0.09 | 1.29 (0.71–2.37), P=0.4 | NR | NR | | | ER−/PgR− | NR | 0.90 (0.65–1.25), P=0.5 | NR | NR | | | ER unknown | NR | NR | 0.79 (0.55–1.14) | NR | | | ER unknown/PgR unknown | NR | 0.96 (0.64–1.44), P=0.8 | NR | NR | | | | |
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| Comparison | LET vs. TAM | ANA vs. TAM | | | N | 3650 | 1856 | | | Median follow-up | 51 months | 68 months | | | ER+ | 0.72 (0.60–0.86) | NR | | | ER+/PgR+ | 0.70 (0.57–0.85) | 0.72 (0.52–1.01) | | | ER+/PgR− | 0.84 (0.54–1.31) | 0.68 (0.40–1.17) | | | | |
The results of this study also demonstrated the superiority of central versus local assessments of receptor status. Eighty-seven patients whose tumors were characterized locally as ER+ and then re-characterized centrally as ER− had poor outcomes (3-year DFS, 69%), with a DFS rate similar to those classified locally and centrally as ER− (62%) [18]. The difference in 3-year DFS with local versus centrally assessed PgR was less clear (local positive/central negative=86%, local negative/central negative=90%). However, when the analysis of DFS was performed after revision, patients erroneously characterized as HR+ locally had worse 3-year DFS (65%) versus those who remained HR+ by local and central assessments (91%) [18]. The ATAC trial was originally designed as a three-arm study evaluating the efficacy and safety of ANA (1mg daily p.o.), TAM (20mg daily p.o.), or ANA+TAM as initial adjuvant therapy in PMW with localized breast cancer following surgery [13]. The ANA+TAM arm was closed early in the course of the trial because of lack of efficacy, and subsequent analyses have focused on the ANA and TAM monotherapy arms at median follow-ups of 68 and 100 months, including analyses of the ITT and the HR+ population [13], [51]. At the 100-month analysis, the benefit in time to recurrence (TTR) was examined in the large ER+/PgR+ subgroup and the smaller ER+/PgR− subgroup via local HR assessment. This analysis showed significant heterogeneity between these subgroups (P=0.001), with a larger benefit of ANA in the latter subgroup (HR, 0.42; 95% CI, 0.31–0.58) compared with the former (HR, 0.87; 95% CI, 0.74–1.02) [51]. Similar findings for TTR were reported in a hypothesis-generating retrospective study of ATAC (Table 2). In the large population of ER+/PgR+ patients (n=5709), the reduction in breast cancer event risk (16%) was not significant (P=0.07), whereas in the smaller population of ER+/PgR− patients (n=1372), the reduction in risk (57%) was significant (P<0.001) [19]. Thus, whereas the benefit of ANA over TAM was noted in both subgroups, the benefit was substantively larger for the subgroup of ER+ patients with PgR− status. Kaplan-Meier analysis revealed that this difference in response resulted from patients on TAM in the ER+/PgR− groups faring substantively worse than those with ER+/PgR+ status [19]. A limitation of this study was the fact that the analysis was conducted based upon locally assessed receptor status with varying assessment methodologies and receptor positivity thresholds. The TransATAC project was therefore initiated in an effort to collect tumor blocks from women with HR+ disease participating in ATAC, for central assessment [50]. Among the 5880 patients assigned to monotherapy with ANA or TAM, tumor blocks were received for 2006 patients, predominantly from the United Kingdom. The populations of the TransATAC and the HR+ patients in ATAC differed with regard to the proportion of node-negative patients (66% vs. 60%, respectively) and the use of adjuvant chemotherapy (9% vs. 21%, respectively) [50]. Results were obtained from 1856 patients; 1782 (30% of monotherapy arms) patients were characterized as ER+ and/or PgR+ via central analysis and constituted the TransATAC Tissue Resource Group (TRG). Importantly, unlike the earlier findings of the hypothesis-generating study in HR+ patients from ATAC (Table 2), no difference between the PgR+ and PgR− patients was seen for the TransATAC TRG central analysis (HR for TTR, 0.72 and 0.68, respectively) (Table 3) or for the TransATAC local assessment (HR for TTR, 0.67 and 0.57, respectively) [50]. The patient populations for both TransATAC assessments were different than the overall population of ATAC; therefore, results from this retrospective trial are not representative of ATAC trial. While the data cannot be extrapolated to the ATAC population as a whole, results of the TransATAC study showed that PgR, HER2, and to a lesser degree, ER, were similar prognostic indicators in TAM- or ANA-treated patients and showed a benefit of ANA over TAM regardless of these prognostic factors; no predictive factor was identified for a differential effect between treatments, although some of the subgroups were small, and results cannot be considered conclusive [50]. Comparing the HR+ population in ATAC with the TransATAC group, there was a significant benefit in TTR (HR, 0.74; P=0.002 and HR, 0.69; P=0.008, respectively) and recurrence was smaller in both arms for the TransATAC population compared with ATAC [50]. ER status was marginally associated with TTR in TransATAC, with lower levels being associated with shorter TTR; the effect was less strong in TAM-treated patients (P=0.078) compared with ANA-treated (P=0.009) patients [50]. For TTR, there was no significant interaction between ER level and treatment. PgR levels, by comparison, were strongly correlated with TTR, with lower levels associated with shorter TTR; this was true for TAM- (P=0.0012) and more strongly for ANA-treated (P<0.0001) patients [50]. For TTR, there was no significant interaction between PgR levels and treatment. Taken together, the results of the BIG 1-98 central review of receptor status clearly suggest that the benefit of LET over TAM is consistent, irrespective of PgR status. In contrast, results from ATAC concerning PgR status are conflicting and prohibit any clear conclusions. Therefore, current findings demonstrate that PgR status should not be used as a discriminating factor in the selection of patients for initial adjuvant therapy with LET [48]. As previously stated, HER2 status also has been examined using central assessment in BIG 1-98. Among the patients assigned to the monotherapy arms, 3650 were assessable for central review, and 257 (7%) of these were identified as HER2+ [48]. Among the 3533 patients confirmed by central assessment to be ER+, 239 (6.8%) were HER2+; as expected, DFS was poorer in patients with HER2+ versus HER2− disease (HR, 2.09; 95% CI, 1.59–2.76), with a 4-year DFS of 75% versus 88% in these respective groups [48]. The benefit in DFS of LET over TAM was again retained (HR, 0.72; 95% CI, 0.59–0.87 and HR, 0.62; 95% CI, 0.37–1.03 in patients with HER2− and HER2+ disease, respectively), regardless of HER2 status. There was no statistical evidence of heterogeneity in the treatment effect according to HER2 status (P=0.60 for interaction) [48]. In ATAC, HER2 positivity was also associated with shorter TTR in both TAM and ANA-treated patients at 5 years (P=0.0018 and P<0.0001, respectively). There was no evidence for a greater differential benefit for ANA over TAM in HER2+ patients, even if the number of events in the HER2+ group was small (N=44 events) [50]. Overall, both LET and ANA provided a benefit compared with TAM, regardless of HER2 status, and, similar to PgR status, HER2 status should not be used as a discriminating factor in the selection of patients for initial adjuvant therapy. Central pathology assessment has also been conducted for Ki67 labeling index in BIG 1-98. In this study, higher Ki67 labeling index was associated with poorer DFS (HR, high vs. low, 1.8; 95% CI, 1.4–2.3), and the magnitude of treatment effect with LET versus TAM was greater for those with high Ki67 labeling index (HR, 0.53) compared with those with low Ki67 labeling index (HR, 0.81; interaction P=0.09) [52]. Thus, Ki67 was confirmed as a prognostic factor in BIG 1-98, and those with high Ki67 labeling index may particularly benefit from initial adjuvant LET therapy. 3.4. Neoadjuvant therapy Preoperative neoadjuvant therapy (i.e., therapy intended to improve success of surgery via a reduction in tumor size) with LET (2.5mg daily p.o.) has been compared with TAM (20mg daily p.o.) in the P024 trial, a randomized, double-blinded study in 337 PMW with ER+ and/or PgR+ disease whose tumors were not eligible for breast-conserving surgery at baseline [53]. LET was significantly superior to TAM in terms of overall objective response rate (55% vs. 36%, P<0.001), with more breast-conserving surgery possible in the LET arm (45% vs. 35%; P=0.022). Of note, a separate study reported that unlike TAM (20mg daily p.o.), LET (2.5mg daily p.o.) was effective in achieving a clinical response, even among patients with low ER expression (Allred) scores (Fig. 3A) [54]. This suggests that LET is more effective than TAM regardless of the level of ER expression. The relationship with PgR status was more complex, with both LET and TAM producing higher responses at intermediate PgR scores, whereas lower or higher scores had a lesser chance of responding (Fig. 3B). The response rate for HER2+ tumors treated with TAM was lower than that of HER2− tumors (17% vs. 40%; P=0.045). By comparison, there was no apparent effect of HER2 status on responses to LET (for HER2−, 53%; for HER2+, 69%; P=0.250) [54]. In a different study, the prospective audit of patients (N=182) with ER-rich breast cancers (Allred score between 5 and 8) showed that 69.8% achieved a complete or partial response with a 3-month course of neoadjuvant LET (2.5mg daily p.o.) [55]. Both clinical and ultrasound tumor volumes were reduced by over two-thirds in patients on neoadjuvant LET, regardless of HER2 status [56]. In a separate evaluation of tumor proliferation at baseline and the end of treatment in 185 patients in the P024 trial, LET was significantly more effective than TAM in inhibiting tumor proliferation (reduction in geometric mean Ki67, 87% vs. 75%; P=0.0009), and the benefit of LET over TAM was observed regardless of HER2 or HER1 overexpression (for HER1/2−, 86% vs. 79%, P=0.0149; for HER1/2+, 88% vs. 45%, P=0.0018) [57]. In contrast, HER1/2+ tumors as a group exhibited resistance to the antiproliferative effects of TAM. In a further combined analysis (N=305) of the P024 cohort and 106 additional samples from patients treated with preoperative LET in the Edinburgh Breast Unit, HER2 expression, as detected by fluorescence in situ hybridization (FISH) in 28 samples (9.2%), did not affect the clinical response to LET [58]. While HER2 FISH+ tumors showed significantly higher histologic grade (P=0.0088), pretreatment Ki67 (P<0.005), and less Ki67 suppression with LET (P=0.0001) compared with HER-2 FISH− tumors, the benefit seen with neoadjuvant LET was not affected by HER2 expression; HER2 FISH+ versus HER2 FISH− tumors showed similar response by clinical measurement (71% vs. 71%; P=0.98), ultrasound (47% vs. 54%; P=0.61), or mammography (44% vs. 47%; P=0.79) [58] There were similar findings in the smaller TAM-treated cohort with regard to tumor characteristics [58]. Overall, the analysis showed that while HER2 expression did not appear to compromise the efficacy of LET in the neoadjuvant setting, the presence of HER2 was nonetheless associated with some resistance to LET (although less than seen with TAM) at the level of cell proliferation [58]. Neoadjuvant treatment with ANA has not demonstrated a significant benefit compared with TAM. The Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) trial compared neoadjuvant ANA (1mg daily p.o.) with TAM (20mg daily p.o.) or the combination of ANA+TAM in PMW with nonmetastatic ER+ invasive breast cancer [59]. Patients were randomly assigned to receive 12 weeks of primary treatment followed by surgery and a subsequent 5 years of ANA. There were no significant differences between the groups in objective response rates (37%, 36%, and 39%, respectively); on logistic regression, significantly more responders had higher ER expression levels (P=0.02) However, while ANA showed no benefit compared with TAM, there were differences in HER2+ patients; the objective response rate in patients treated with ANA was 58% relative to 22% with TAM (P=0.18). The lack of significance may be the result of an underpowered analysis due to the small number of patients [59]. Another similar study of 24 women treated with neoadjuvant ANA (1 or 10mg daily p.o.) for 12 weeks showed no differences between low (0/1+) and high (3+) HER2+ tumors with regard to clinical response, changes in proliferation (Ki67 values), or PgR expression [60]; these data suggest that ANA is equally effective in HER2+ and HER2− breast cancers in the neoadjuvant setting. It should also be noted that the course of primary treatment in the IMPACT trial was shorter than in P024 trial (16 vs. 12 weeks), and this could have affected the difference in terms of activity between the study arms. Both the P024 and IMPACT trials showed an early effect of AIs in reducing proliferation index (Ki67). Notably, on-treatment Ki67 measurements were superior predictors of long-term outcome than pretreatment levels. In the IMPACT trial, decrease of Ki67 at both 2 and 12 weeks was greater with ANA than with either TAM or the combination of ANA and TAM. This result mirrored the improved recurrence-free survival of ANA over the other two arms in the much larger ATAC trial, and required far less follow-up: 2 or 12 weeks for IMPACT versus 31 months for the first outcome data from ATAC. A model to predict relapse risk has been developed using results from the P024 trial. This model integrated pathological tumor size, nodal status, Ki67 level, and ER Allred score into a preoperative endocrine prognostic index (PEPI) score [61]. The PEPI model was used to define three risk groups (risk score 0, 1–3, and >4) that were respectively associated with relapse risks of 10%, 23%, and 48% (P<0.001) and breast cancer death rates of 2%, 11%, and 17% (P<0.001) [61]. The PEPI model was then validated in the similarly designed IMPACT study, and the results showed that the model produced a significant separation of the three PEPI risk groups (P=0.002). The findings of this study thus distinguish between PEPI group 1 and PEPI group 3, respectively, to define a patient group with a very low risk of relapse that would not benefit from further treatments such as chemotherapy, and a group of patients who have a significantly higher risk for early relapse, more typically like ER− disease, that would subsequently benefit from all appropriate systemic therapies [61]. 3.5. Switch adjuvant therapy: EXE Switch adjuvant trials differ in their design from initial (or upfront) adjuvant trials, such as ATAC and BIG 1-98. Unlike initial adjuvant trials, which randomize patients at the time of surgery and include all breast cancer events, switch trials randomize patients who are alive and disease-free after 2–-3 years of TAM. Although relapses in HR+ patients can occur later, even beyond 5 years, a substantial risk occurs during the first 2–3 years following surgery [43]. In addition, the most common type of recurrence event in this early period is DM, which have a major impact on survival outcomes in women with EBC [44], [45], [46]. Switch trials therefore exclude a critical population of patients from the efficacy analysis, selecting for a recurrence-free, better-prognosis patient population that is substantially different from initial adjuvant trial populations. The IES examined the efficacy and safety of a switch from TAM (20mg daily p.o.) to EXE (25mg daily p.o.), in comparison with continued TAM, in PMW with ER+ or ER-unknown breast cancer who remained disease-free following 2–3 years of treatment with TAM, so as to complete 5 years of endocrine treatment [15]. In this trial (N=4724), most patients (56.5%) were classified as ER+/PgR+, and a smaller percentage were ER+/PgR− or unknown (29.1%). Subgroup analysis from the IES, at 55.7 months of follow-up, generally showed similar benefit for DFS across receptor strata examined in the ER+/unknown population of patients (Table 2), suggesting that switching to EXE after initial TAM therapy is beneficial regardless of the patient's PgR status [15]. 3.6. Sequential adjuvant therapy: LET The BIG 1-98 trial was designed to address several questions, including the use of sequential therapy with LET and TAM in either order. However, unlike the IES, the BIG 1-98 study examined all events from the time of surgery onward. Patients were assigned at surgery to one of four treatment groups, each for 5 years: TAM monotherapy, LET monotherapy, or sequential treatment with 2 years of one agent followed by 3 years of the other. The sequential treatment analysis (LET monotherapy vs. TAM followed by LET, and LET monotherapy vs. LET followed by TAM), involving 6182 patients, was presented at the 31st Annual San Antonio Breast Cancer Symposium [47]. The analysis was designed to demonstrate superiority with either sequential approach, but at a median follow-up of 71 months, there were no significant differences in DFS, OS, and time to distant recurrence between monotherapy and sequential arms. This suggested that neither sequential approach was superior to LET monotherapy for 5 years. 3.7. Extended adjuvant therapy: LET Extended adjuvant therapy (i.e., following the full course of TAM) has been examined in the MA.17 trial. In this trial, PMW with HR+ disease were randomized to treatment with LET (2.5mg daily p.o.) or placebo for 5 years following 4.5–6.0 years of treatment with TAM [62]. When the first interim efficacy analysis showed a significant improvement in DFS for patients assigned to LET, the trial was stopped prematurely, and patients on placebo were offered the option to cross over to LET. In the updated analysis, which included all events occurring up to the time of unblinding (median follow-up, 2.5 years), prespecified subgroup analysis demonstrated superiority of LET over placebo in the subgroup of HR+ patients (defined in the trial as ER+, PgR+, or ER+/PgR+; 97.4% of all patients), with a significant benefit in DFS (HR, 0.58; 95% CI, 0.45–0.76; P<0.001) [62]. A subsequent retrospective subgroup analysis according to receptor status demonstrated a benefit of LET over placebo in the large subgroup of patients (n=3809) with ER+/PgR+ disease (51% improvement), as well as the smaller subgroup of ER−/PgR+ patients (44% improvement). However, the smaller subgroup of ER+/PgR− patients did not appear to benefit from LET in terms of DFS (Table 2) [20]. There was also a 47% improvement in distant DFS (DDFS; HR, 0.53) and a 42% improvement for OS (HR, 0.58) for patients in the ER+/PgR+ subgroup. Similar to the findings with DFS, patients in the ER+/PgR− group did not appear to benefit from LET in terms of DDFS (HR, 1.25) or OS (HR, 1.52), although the number of patients was likely too small to draw conclusions in these latter endpoints. The difference between the ER+/PgR+ and ER+/PgR− groups was significant for DFS (P=0.02) but not for DDFS (P=0.06) or OS (P=0.09) [20]. Although these data should be considered as hypothesis-generating and requiring future confirmation, they suggest a significant survival benefit of extended adjuvant LET in the large subgroup of ER+/PgR+ patients, whereas the smaller group of ER+/PgR− patients does not appear to benefit from extended adjuvant LET [20]. 4. Strategies addressing resistance to endocrine therapy As noted earlier, the amplification of growth factor receptors such as HER2 in breast cancers may lead to the development of resistance to endocrine therapies such as TAM. As TAM can have both estrogen-antagonist and estrogen-agonist properties, it has been hypothesized that the expression of HER2 in breast cancer cells leads to a loss of the estrogen antagonist activity [8]. These findings suggest the importance of maximizing the suppression of estrogen activity (e.g., with an AI) and of enhancing the effect through combination with growth factor inhibitors, and in fact, this strategy has been the focus of recent clinical trials [8]. 4.1. AIs and trastuzumab Trastuzumab is an antibody developed to specifically target and inhibit HER2. The initial protocol of a 4mg/kg i.v. loading dose followed by 2mg/kg i.v. weekly was amended to an 8mg/kg i.v. loading dose followed by 6mg/kg i.v. every 3 weeks, to improve patient compliance. Trastuzumab has been combined with LET (2.5mg daily p.o.) in a phase 2 study of 33 patients with ER+ and/or PgR+, HER2+ disease [63]. Efficacy among the evaluable patients (n=31) showed an objective response rate (complete response plus partial response) of 26% and a clinical benefit rate of 52%, with a median time to progression (TTP) of 5.8 months [63]. The TrAstuzumab in Dual HER2 ER-Positive Metastatic breast cancer (TAnDEM) study, a first-line phase 3 trial, evaluated the efficacy and safety of trastuzumab (4mg/kg i.v. loading dose followed by 2mg/kg i.v. weekly) in combination with ANA (1mg daily p.o.; n=103) versus ANA alone (n=104) in PMW with HR+, HER2+ MBC. In this trial, progression free survival (PFS; 4.8 vs. 2.4 mo; P=0.0016), clinical benefit rate (42.7% vs. 27.9%; P=0.026), and TTP (4.8 vs. 2.4 mo; P=0.0007) were significantly improved in the combination arm, and OS trended better (28.5 vs. 23.9 mo; P=0.325), despite the crossover of >50% of patients in the ANA arm to the combination arm upon disease progression [64]. Although further study is needed, the combination of AIs with trastuzumab appears to be an interesting option for patients with HR+/HER2+ disease. 4.2. AIs and kinase inhibitors Lapatinib (GW572016), a selective inhibitor of both the HER1 and HER2 tyrosine kinases, has been shown to inhibit the growth of breast cancer cell lines that overexpress HER2 as well as cell lines that have been selected for trastuzumab resistance [65]. The EGF30008 trial examined the combination of lapatinib (1500mg daily p.o.) and LET (2.5mg daily p.o.) versus LET alone as first-line therapy in PMW with HR+ (ER+ and/or PgR+) MBC [66]. Of the ITT population (N=1286), 219 (17%) patients were HER2+, 952 (74%) were HER2−, and 115 (9%) were HER2-unknown. Results in HER2+ patients showed a significant 29% reduction (HR, 0.71; 95% CI, 0.53–0.96; P=0.019) in the risk for disease progression and an improvement in median PFS from 3.0 to 8.2 months with lapatinib and LET combination therapy. In the HER2+ population, combination therapy was also associated with a significant improvement in the clinical benefit rate (48% vs. 29%; P=0.003). Adverse events were predictable and manageable, and long-term cardiotoxicity was not observed. Interestingly, exploratory analysis suggested that combination therapy may benefit patients with HR+/HER2− MBC as well. In the ITT population, of which 83% of patients had HER2− or HER2-unknown disease, PFS was significantly improved (HR, 0.86; 95% CI, 0.76–0.98; P=0.026). Thus, the EGF30008 trial demonstrates that lapatinib plus LET is a valuable first-line oral treatment approach for PMW with HR+, HER2+ MBC. Ongoing trials are investigating the efficacy and safety of this combination in patients with operable stage I–III breast cancer [67] and as neoadjuvant therapy for early breast cancers [68]. Preliminary findings of the latter study (N=37 patients randomized) have shown mild and manageable toxicity associated with the regimen and no early cardiac toxicity, with clear tumor shrinkage obtained [69]. The combination of other receptor tyrosine kinase inhibitors, such as AEE788, with AIs or TAM is also being investigated. Studies have shown AEE788 to be effective in suppressing tumor cell line growth in combination with TAM or LET without interfering with ER activity, suggesting that the combination therapy allows for a separate mechanism to additively inhibit proliferation [70]. 4.3. AIs and everolimus RAD001 (everolimus) is a specific inhibitor designed to target the mammalian target-of-rapamycin (mTOR) signaling molecule, which plays an integral role in multiple growth factor signaling pathways [71]. In cell lines, everolimus causes a concentration-dependent reduction in proliferation irrespective of ER or HER2 status. Moreover, when used in combination with either TAM or LET, everolimus enhanced the antiproliferative effect of either agent on its own [71]. Of note, in tumor xenografts expressing aromatase (MCF7-AROM), TAM with everolimus provided no added benefit over either agent alone, whereas the combination of LET with everolimus resulted in the greatest reduction in tumor volume [71]. In a study of 270 PMW with ER+, T2 or greater breast cancer, the combination of LET (2.5mg daily p.o.) and everolimus (10mg daily p.o.) resulted in a greater clinical response (68% vs. 59%; P=0.062) and ultrasound response (58% vs. 47%; P=0.035) compared with LET and placebo, and cell cycle response was also significantly better with the combination of LET with everolimus [72]. 5. Conclusions Multiple studies have indicated some prognostic and predictive value for ER, PgR, and HER2 status in EBC. Indeed, the use of endocrine therapy with either TAM or the AIs is limited to HR+ disease, which has been defined as ER+ and/or PgR+ status of the primary tumor. IHC methods have replaced quantitative analyses such, as ligand binding assays as the gold standard for HR assessment [73]. With modern IHC methods, it has been reported that ER− tumors are so frequently PgR− (99.5%) that PgR testing is of no benefit. Thus, the original reason for performing PgR testing, to determine whether patients with ER− tumors might benefit for hormonal therapy, is no longer valid provided we can limit the false-negative rate of ER expression [26]. At present, hormonal treatment remains a recommended therapy for all three of these (HR+) groups, and efforts should be made by pathologists to enhance the accuracy and reproducibility of HR status analysis. Most major guidelines and consensus statements, including those of the American Society of Clinical Oncology, European Society for Medical Oncology, National Comprehensive Cancer Network, and St. Gallen, now recognize the value of ER, PgR, and HER2 assessment at diagnosis, and some (e.g., St. Gallen) have recognized as logical, although still unproven, the utility of trastuzumab in addition to endocrine therapy and/or initial adjuvant therapy with an AI over TAM in patients with HER2+ disease [74]. In general, however, none of the current guidelines have recommended discriminating between the use of AIs or TAM in patients with HR+ disease on the basis of PgR and/or HER2 status [74], [75], [76], [77], [78]. This may be reasonable, given the recent results of additional analyses from BIG 1-98, which show an equivalent respective efficacy of LET over TAM irrespective of PgR or HER2 status. Analyses of receptor status with ANA therapy are less clear, as ATAC showed a significant benefit for patients with ER+/PgR− status, whereas local and central review in TransATAC did not reproduce these findings and found no benefit based on PgR status. The discrepancies between the analyses highlight that the population in TransATAC was not representative of the overall ATAC population, and no conclusions can be clearly drawn. In contrast, in BIG 1-98, the central analysis was conducted with material obtained prospectively from a substantive proportion of patients and clearly suggests a benefit of LET over TAM regardless of PgR and HER2 status. These factors should thus not be used to make treatment decisions in patients who are otherwise candidates for adjuvant therapy with LET. Nevertheless, there is evidence that ER+ patients with PgR− phenotype are more likely to display an increased growth factor signaling activity, a more aggressive behavior, and a higher potential for TAM resistance. In such patients, the use of the most effective hormonal treatment upfront (i.e., an AI as opposed to TAM) would seem most appropriate. In the near future, the use of growth factor-targeted therapies in combination with AIs also may be a feasible option for patients displaying resistance to endocrine therapy. Reviewers Dr. Filippo Montemurro, Institute for Cancer Research and Treatment (IRCC), Unit of Medical Oncology, Strada Provinciale 142, I-10060 Candiolo, Italy. Prof. Ian Ellis, Professor of Cancer Pathology, City Hospital, University of Nottingham, Molecular Medical Sciences, Department of Histopathology, Hucknall Road, Nottingham, NG5 1PB, United Kingdom. Conflict of interest Dr. Fabio Puglisi indicated a financial interest that is relevant to the subject matter under consideration in this article. He attended an Advisory Board meeting organized by Novartis Pharmaceuticals Corporation, being compensated for his participation. Dr. Alessandro Marco Minisini has no conflicts of interest to disclose. Acknowledgement Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals. We thank Maria Soushko, PhD, for medical editorial assistance with this manuscript. References [1]. [1]Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007;18:581–592. MEDLINE |
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[78]. [78]National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Breast Cancer. Version 1.2009. www.nccn.org/professionals/physician_gls/PDF/breast.pdf [accessed 08.31.09]. Fabio Puglisi is a researcher in Medical Oncology and senior staff member of the Department of Medical Oncology, University Hospital of Udine, Italy. He received his degree in medicine (cum laude) from the University of Palermo, Italy in 1993. His post-graduate specialty was in oncology (University Hospital of Udine, 1997). He was a visiting research fellow in both the United Kingdom (City Hospital NHS Trust, Nottingham) and Belgium (Institut Jules Bordet, Brussels). Dr. Puglisi earned a PhD in Diagnostic Quantitative Pathology from the University of Siena, Italy in 2002. His research interests include breast cancer treatment and prognostic and predictive factors. Dr. Puglisi is an active member of the American Society of Clinical Oncology, International Breast Cancer Study Group, Italian Association of Medical Oncology, and Gruppo Italiano Mammella. Alessandro Marco Minisini is a staff member of the Medical Oncology Department of the University and General Hospital of Udine, Italy. Dr. Minisini received his degree in medicine from the University of Udine, Italy in 2000. He undertook his post-graduate training in oncology at the same institution and spent 1 year as a clinical research fellow at the Institut Jules Bordet in Brussels, Belgium. He received his PhD in 2008. Dr. Minisini's research interests include the evaluation of new predictive and prognostic factors in breast cancer therapies. He is member of the Italian Association of Medical Oncology. Department of Medical Oncology, University Hospital of Udine, Udine, Italy  Corresponding author at: Department of Medical Oncology, University Hospital of Udine, Piazzale S.M. Misericordia, 33100 Udine, Italy. Tel.: +39 0 432 559304 09; fax: +39 0 432 559305.
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